PROJECT SUMMARY ? ABSTRACT This application seeks to understand how the brain, through signals delivered via sympathetic neurons, controls immune function. The sympathetic nervous system controls a variety of cellular and metabolic functions and plays a critical role in the flight or fight response. The adrenergic class of neurotransmitter receptors binds to nor-epinephrine secreted by sympathetic neurons and is a target of various pharmacological agonists and antagonists used in humans. Very little is known about how this pathway interfaces with the immune system. We recently found selective expression of the ?2-adrenergic receptor (ADRB2) on human CD8+ memory T cells, and it is also expressed in murine CD8+ T cells. Signaling through this receptor significantly suppressed various effector T cell functions including cytokine secretion and lytic activity. Further, CD8+ CTLs lacking the ADRB fail to generate memory cells following infection with vesicular stomatitis virus. Given the importance of this pathway in regulating multiple physiological processes, we wished to determine the role of the ADRB2 in regulating the major functions of adaptive cytolytic T cells of the immune system. Aim 1 will determine how intrinsic ADRB2 signaling regulates the development and function of both effector and memory CD8+ CTLs in response to intracellular infections. Aim 2 will identify the molecular pathway that drives ADRB2-mediated memory development. Finally, Aim 3 will determine how long-acting ?-agonist drugs alter the course of a primary and secondary immune response to flu infection. These studies will inform us on the role of the sympathetic nervous system in regulating cytolytic T cell function and how pharmacological agonists alter those responses.